Outcomes of SGLT-2i and GLP-1RA Therapy Among Patients With Type 2 Diabetes and Varying NAFLD Status

Key Points Question Are sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) associated with reduced cardiovascular risk in patients with type 2 diabetes and concomitant nonalcoholic fatty liver disease (NAFLD)? Findings In this population-based cohort study, GLP-1RA and SGLT-2i therapy were associated with reduced risk of major adverse cardiovascular events in patients with T2D and across baseline NAFLD status. Moreover, SGLT-2i therapy was associated with reduced risk of hospitalization for heart failure. Meaning These results support the current guidelines that recommend GLP-1RA as the first-line of therapy for patients with T2D and NAFLD and highlight the potential of SGLT-2i as a promising option for cardiovascular disease prevention regardless of NAFLD status.

Other outcomes were defined as ≥1 diagnosis from an inpatient setting or ≥2 independent diagnoses within 180 days from an outpatient setting; the first date was used as the event date for the latter definition.
Other outcomes were defined as ≥1 diagnosis from an inpatient setting or ≥2 independent diagnoses within 180 days from an outpatient setting; the first date was used as the event date for the latter definition.

ICD-10 codes: N17
Genital infection Defined as hospitalized the primary (e.g., most accountable) and secondary position.
Other outcomes were defined as ≥1 diagnosis from an inpatient setting or ≥2 independent diagnoses within 180 days from an outpatient setting; the first date was used as the event date for the latter definition.
Other outcomes were defined as ≥1 diagnosis from an inpatient setting or ≥2 independent diagnoses within 180 days from an outpatient setting; the first date was used as the event date for the Other outcomes were defined as ≥1 diagnosis from an inpatient setting or ≥2 independent diagnoses within 180 days from an outpatient setting; the first date was used as the event date for the latter definition.
Other outcomes were defined as ≥1 diagnosis from an inpatient setting or ≥2 independent diagnoses within 180 days from an outpatient setting; the first date was used as the event date for the latter definition.

Sensitivity analysis
The Hepatic Steatosis Index (HSI) represents an effective screening tool for identifying individuals with NAFLD.Its application can aid in the selection of individuals who would benefit from liver ultrasonography, as well as guide decisions regarding the implementation of lifestyle modifications to manage the condition.
HSI ≥36 can be used as proxy indicator for presence of NAFLD with PPV of 85.9% † .
eAppendix 2. Description of Sensitivity Analyses

Discussions
The findings across a range of sensitivity analyses were generally consistent with those of the main analysis in both of SGLT-2i and GLP-1RA cohorts.In particular, we observed the similar results in another model estimating NAFLD, the hepatic steatosis index (HSI), which takes into account sex and type 2 diabetes prevalence.Thus, it is more likely used as an indicator of the robustness of our findings in assessing the CVD effectiveness of glucose lowering medications among patients with type 2 diabetes according to presence or absence of NAFLD.Moreover, similar results were observed in the analysis of restricted cohort within one year of fatty liver index.These results suggested that the duration between the measurement date of the health examination record for NAFLD estimation and cohort entry had a limited impact on the results.This study evaluated the safety profiles of two novel antidiabetic drugs of SGLT-2i and GLP-1RA among patients with NAFLD.This study's association between SGLT-2i and genital infection was in line with previous research (incidence rate ratio 3.50, 95% CI 3.09-3.95)*.With regards to DKA, our results showed higher estimates of DKA among patients with NAFLD, indicating that abnormal hepatic glucose metabolism may further increase the risk of DKA with SGLT-2i in this subgroup, which are corroborated by a metaanalysis of seven large-scale randomized trials (RR 3.54, 95% CI 0.82-15.39)† .Meanwhile, GLP-1RA was associated with a decrease risk of hypoglycemia in the overall population, and the point estimate for hypoglycemia in patients with NAFLD were lower than those of without NAFLD.This effect could be attributed to the reported improvement of NAFLD by GLP-1RA in other studies, which may lead to an improvement in the blood glucose control function of the liver ‡ .Taken together, the overall safety profiles of both SGLT-2i and GLP-1RA among patients with NAFLD were favorable.However, further research is warranted to establish conclusive evidence on the association between these novel antidiabetic drugs and the risk of adverse events in this subgroup. [References] * fracture Defined as hospitalized the primary (e.g., most accountable) and secondary position.
the primary (e.g., most accountable) and secondary position.Required records of in-hospital admission or emergency room visits on the date of outcome occurrence ICD-10 codes: E111, E131, E141 Hypoglycemia Defined as hospitalized the primary (e.g., most accountable) and secondary position.Required records of in-hospital admission or emergency room visits on the date of outcome occurrence ICD-10 codes: E160, E161, E162, E1163, E1363, E1463 Pancreatitis Defined as hospitalized the primary (e.g., most accountable) and secondary position.